High Tolerance Research Articles

Retrospective analysis of adherence and persistence of encorafenib in combination with cetuximab among patients with BRAF metastatic CRC in the United States (US).

64 Background: The BRAF V600E mutation (BRAF-m) occurs in approximately 7% of patients with metastatic CRC (mCRC). Encorafenib (enco) in combination with cetuximab (cetux) was approved in April 2020 as the first targeted regimen for the treatment of adult patients with mCRC with BRAF-m. The purpose of this study is to analyze the post-approval real-world persistence and adherence to treatment with enco in combination with cetux or with panitumumab (pani), an alternative EGFR, in mCRC, based on a claims database in the US. Methods: This was a retrospective cohort study in the IQVIA PharMetrics Plus claims database (2013-2022). Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent EGFR (cetux or pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included. Patients were excluded if they had a record of melanoma or non-small cell lung cancer during the year before index date, were enrolled in a clinical trial any time after the CRC diagnosis date or did not have a treatment regimen starting on or after CRC diagnosis date. Index date was the date of first treatment of enco + EGFR during the identification period (4/1/2020-3/31/2022). Patient demographics and disease characteristics were assessed at baseline, adherence (measured as at least 80% of days covered) and persistence (measured as time to discontinuation by Kaplan-Meier method) were estimated during the follow-up period. Results: 125 patients were included. Median (Q1 [1st quartile], Q3 [3rd quartile]) age at index was 58 (49, 63) years and 52.0% were female. Metastases were present in 3 or more sites in 60.8% of the patients, in 1 or 2 sites in 37.6%. The 2011 Modified Quan Charlson Comorbidity Index was 0 for 44.8% of the patients, 1-2 for 39.2%, and 3 or more for 16.0%. Most patients received cetux as their EGFR combined with enco (77.6%). Adherence to enco + EGFR was high (85.6%); enco + cetux vs. enco + pani: 89.7% vs. 74.1%. Median (Q1, Q3) proportion of time on cetux while on enco was 87.9% (77.9%, 94.3%) and median (Q1, Q3) proportion of time on pani while on enco was 79.9% (70.0%, 90.0%). Median (95% confidence interval) time to enco regimen discontinuation during follow-up was 6.2 (4.9–8.8) months. Conclusions: This up-to-date study provides current real-world evidence on the use of enco + EGFR in mCRC BRAF-m patients in the US. The results show high levels of adherence to the treatment, suggesting high tolerability to encorafenib, and persistence consistent with clinical trial evidence.

Scalable large area perovskite solar cell modules fabricated with high humidity tolerance by vacuum deposition

Vacuum deposition is promising for large-area, high-throughput production of perovskite solar cells (PSCs). However, the strict low humidity control increases the costs for manufacturing facilities and hinders the large-scale production of PSCs. In this work, a sequential deposition method was used to prepare the perovskite intermediate phase, and the impact of ambient humidity was studied during the annealing process. It is shown that proper humidity has a positive effect on the perovskite layer, which is conducive to accelerate the reaction between organic salts and PbI2 and improve the surface morphology of the film. The perovskite annealing under 55 % relative humidity exhibits fewer defects and faster carrier transport kinetics. The resulting PSCs, with all layers fabricated adopting vapor deposition, yield a power conversion efficiency (PCE) of 15.01 % for the large area modules of 100 cm2 (active area 64.8 cm2). More impressively, the PCE of the unpackaged cell modules remained above 80 % after being placed in ambient air for 1200 h. The results open a promising way for scalable fabrication of humidity-tolerant large-area perovskite solar cell modules and shed light on the industrial production of PSCs.

Conversion of a Small-Size Passenger Car to Hydrogen Fueling: 0D/1D Simulation of EGR and Related Flow Limitations

Hydrogen is seen as a prime choice for complete replacement of gasoline so as to achieve zero-emissions energy and mobility. Combining the use of this alternative fuel with a circular economy approach for giving new life to the existing fleet of passenger cars ensures further benefits in terms of cost competitiveness. Transforming spark ignition (SI) engines to H2 power requires relatively minor changes and limited added components. Within this framework, the conversion of a small-size passenger car to hydrogen fueling was evaluated based on 0D/1D simulation. One of the methods to improve efficiency is to apply exhaust gas recirculation (EGR), which also lowers NOx emissions. Therefore, the previous version of the quasi-dimensional model was modified to include EGR and its effects on combustion. A dedicated laminar flame speed model was implemented for the specific properties of hydrogen, and a purpose-built sub-routine was implemented to correctly model the effects of residual gas at the start of combustion. Simulations were performed in several operating points representative of urban and highway driving. One of the main conclusions was that high-pressure recirculation was severely limited by the minimum flow requirements of the compressor. Low-pressure EGR ensured wider applicability and significant improvement of efficiency, especially during partial-load operation specific to urban use. Another benefit of recirculation was that pressure rise rates were predicted to be more contained and closer to the values expected for gasoline fueling. This was possible due to the high tolerance of H2 to the presence of residual gas.

Compact all-optical half adder based on topology optimization

We proposed an inverse-designed compact half adder on a silicon-on-insulator platform with a footprint of 2µm×2µm. The optical power of SUM and CARRY is controlled by different input combinations, according to the truth table of a half adder. Topology optimization is applied to cope with multiple objective functions in such a combinational logic circuit. The transmittance at 1550 nm for CARRY with 11 input is 170.2%, with extinction ratios (ERs) of 27.1 and 5.8 dB for SUM and CARRY, respectively. The SUM and CARRY outputs have ERs over 22.0 dB and 5.7 dB from 1515 nm to 1600 nm. Phase condition and morphology analysis show that the device has high tolerance on phase fluctuation and fabrication. The proposed device with compact footprint, low insertion loss, and large bandwidth presents a novel, to the best of our knowledge, approach to achieve all-optical combinational logic circuits with inverse design.

Development of a Standardised International Protocol for Evaluation of the Disinfection Efficacy of Healthcare Laundry Wash Processes

This research aims to develop a standardised protocol for monitoring the disinfection efficacy of healthcare laundry processes in view of numerous differential methodologies currently being employed within the healthcare laundry sector, including agitation and surface sampling for post-laundering decontamination assessment and swatch and bioindicator testing for in-wash-process efficacy. Enterococcus faecium as an indicator species within industrial wash systems is preferable due to its high thermal and disinfectant tolerance. Methods for measuring laundry disinfection were compared; commercially available E. faecium bioindicators and contaminated cotton swatches (loose, in cloth bags or within nylon membranes) were laundered industrially at ambient temperature and microbial recovery determined. E. faecium was lost from cotton during laundering but retained by the bioindicator membrane, which allows disinfection efficacy to be measured without loss of microorganisms from the test swatch. Commercially available bioindicators were only permeable to disinfectants and detergents at ≥60 °C. Subsequently, polyethersulphone membranes for enclosing contaminated swatches were developed for low-temperature laundering, with permeability to industrial laundry chemistries at below ≤60 °C. This study demonstrates that bioindicators are the recommended methodology for laundry disinfection validation. The use of a universal healthcare laundry disinfection methodology will lead to standardised microbiological testing across the industry and improvements in infection control.

Chemoselective Vicinal Dichlorination of Alkenes by Iron Ligand-to-Metal Charge-Transfer Catalysis

AbstractWe report the photocatalytic functionalization of terminal alkenes to vicinal dichlorides by using visible light and FeCl3 as a catalyst, LiCl as a chloride source, and air as an oxidant. The transformation is proposed to be initiated by ligand-to-metal charge-transfer bond homolysis of a Fe–Cl bond, giving a highly reactive chloride radical able to initiate the functionalization of olefins. The process shows high chemoselectivity and broad functional-group tolerance with yields of up to 94% under mild conditions.

Mechanically Robust and Linearly Sensitive Soft Piezoresistive Pressure Sensor for a Wearable Human-Robot Interaction System.

Soft piezoresistive pressure sensors play an underpinning role in enabling a plethora of future Internet of Things (IoT) applications such as human-robot interaction (HRI) technologies, wearable devices, and metaverse ecosystems. Despite significant attempts to enhance the performance of these sensors, existing sensors still fall short of achieving high strain tolerance and linearity simultaneously. Herein, we present a low-cost, facile, and scalable approach to fabricating a highly strain-tolerant and linearly sensitive soft piezoresistive pressure sensor. Our design utilizes thin nanocracked gold films (NC-GFs) deposited on poly(dimethylsiloxane) (PDMS) as electrodes of the sensor. The large mismatch stress between gold (Au) and PDMS induces the formation of secondary wrinkles along the pyramidal-structured electrode under pressure; these wrinkles function as protuberances on the electrode and enable exceptional linear sensitivity of 4.2 kPa-1 over a wide pressure range. Additionally, our pressure sensor can maintain its performance even after severe mechanical deformations, including repeated stretching up to 30% strain, due to the outstanding strain tolerance of NC-GF. Our sensor's impressive sensing performance and mechanical robustness make it suitable for diverse IoT applications, as demonstrated by its use in wearable pulse monitoring devices and human-robot interaction systems.

Amino-Functionalized Graphdiyne Derivative as a Cathode Interface Layer with High Thickness Tolerance for Highly Efficient Organic Solar Cells.

Efficient cathode interfacial materials (CIMs) are essential components for effectively enhancing the performance of organic solar cells (OSCs). Although high-performance CIMs are desired to meet the requirements of various OSCs, potential candidates for CIMs are scarce. Herein, an amino-functionalized graphdiyne derivative (GDY-N) is developed, which represents the first example of GDY that exhibits favorable solubility in alcohol. Utilizing GDY-N as the CIM, an outstanding champion PCE of 19.30% for devices based on the D18-Cl:L8-BO (certified result: 19.05%) is achieved, which is among the highest efficiencies reported to date in OSCs. Remarkably, the devices based on GDY-N exhibit a thickness-insensitive characteristic, maintaining 95% of their initial efficiency even with a film thickness of 25nm. Moreover, the GDY-N displays wide universality and facilitates exceptional stability in OSCs. This work not only enriches the diversity of GDYderivatives, but also demonstrates the feasibility of GDY derivatives as CIMs with high thickness tolerance in OSCs.

CBr4 as a Mild Oxidant-Enabled Oxidation of a sp3 C-H Bond: A Facile Synthesis of the Persistent Iminium Salts of Tetrahydroisoquinolines.

Using CBr4 as a mild oxidant, the direct C-H bond oxidation of N-aryltetrahydroisoquinolines was achieved, giving a series of the corresponding iminium salts in high yields under metal- and photo-free reaction conditions. This reaction is superior in high yields and good functional group tolerance, and the late-stage derivatization showed that these iminium salts can readily be applied to the synthesis of the functionalized THIQs.

The Identification of a Strain for the Biological Purification of Soy Molasses to Produce Functional Soy Oligosaccharides and Optimize Purification Conditions.

Soy molasses is rich in oligosaccharides like sucrose, stachyose, and raffinose, with stachyose and raffinose being functional oligosaccharides. Harnessing soy molasses for the production of functional soy oligosaccharides (FSO) can significantly elevate its value. Biological purification, a method leveraging the selective utilization of different carbon sources by microorganisms, allows for the specific removal of sucrose from soy molasses while preserving stachyose and raffinose, thereby increasing the FSO content. This research identified a yeast named YT312 with strong purification capabilities for soy molasses and optimized the purification conditions. The study revealed that yeast YT312 was Wickerhamomyces anomalus, exhibiting a broad range of growth temperatures and pH levels alongside a high tolerance to glucose, sucrose, and NaCl. Through single-factor and orthogonal experiments, it was established that under specific conditions-0.375% inoculum size, 30 °C fermentation temperature, 150 rpm shaking speed, 10-fold dilution ratio, pH of 7, and 12 h of fermentation-sucrose was completely removed from soy molasses, while functional raffinose and stachyose were retained at rates of 96.1% and 90.2%, respectively. Consequently, W. anomalus YT312 displayed exceptional characteristics for the biological purification of soy molasses and the production of FSO.

High carbohydrate is preferable to high lipid parenteral nutrition in healthy dogs undergoing prolonged sedation.

Parenteral nutrition (PN) is commonly used in intensive care units (ICUs) and is associated with earlier hospital outcome. However, there is scarcity of information about the metabolic effects of PN caloric distribution for dogs. Considering the high tolerance of dogs to lipids and, also, that hospitalized animals usually present insulin resistance, PN formulation with high fat instead high glucose can provide metabolic benefits in this specie. This study evaluated two PN protocols, based on high lipid or high carbohydrate in 12 healthy dogs under sedation/ventilation during 24h. For baseline data, blood samples were collected 24h before the study beginning. After fasting, the dogs were anesthetized and put under mechanical ventilation without energy support for 12h to obtain: daily energy expenditure (DEE), respiratory quotient (RQ), oxygen consumption (VO2), carbon dioxide production (VCO2), lactate, glucose, cholesterol, and triglycerides concentrations. After, the dogs were allocated into two groups: lipid-based energy group (LEG) and carbohydrate-based energy group (CEG). Both groups received the PN infusions at a rate of 3 mL/kg/h for 12h. Blood tests were performed 12, 24, and 48h after infusion's completion. VO2 increased after PN in LEG, increasing energy expenditure compared to CEG. RQ remained close to 1 in CEG, indicating carbohydrate preferential consumption. Triglycerides increased in both groups after propofol infusion, remaining higher in LEG until the end of the evaluation. Glycaemia increased in CEG compared to baseline. In conclusion, both PN protocols can be used in healthy animals undergoing prolonged sedation protocols. However, high lipid PN had higher VO2 and DEE, and resulted in higher triglycerides concentrations and lower glycaemia indexes than carbohydrate, making high carbohydrate PN preferable to high lipid PN. Therefore, for use in critically ill patients, the data obtained in this study should be extrapolated, taking into consideration the specificity of each case.

Stepless space-regulation of topological acoustic controller with high fault tolerance

In this paper, the stepless space-regulation of topological acoustic transmission channels with high fault tolerance is proposed through introducing structural defect dislocations into a topological acoustic controller. Due to the stability of topological order against local disturbance, the acoustic wave transmission is immune to dislocation boundaries with strong stability, and thus the topological acoustic controller has high fault tolerance. By continuous changing the dislocation, the position relationship between the outgoing and incident acoustic signals no longer limited to the integer multiple distance related to the lattice size, and can realize the efficient acoustic energy transmission without energy loss at the fractional multiple distance, that is, the topological controller can realize lossless acoustic energy transmission and reception in arbitrary position relationship. Furthermore, the coupling relationship between the defect dislocation and the topological acoustic channel is explored, which can realize the stepless space-regulation of the lossless channel in the wide band range. In addition, by further introducing multi-layer continuous dislocations, this high-fault-tolerant topological acoustic controller still has strong stability, and multiple error factors do not affect the transmission results, which greatly reduces the difficulty of manufacturing. Finally, the stepless space-regulation of topological acoustic channels and the high-fault-tolerant topological acoustic controller that are easy to manufacture are verified by our experiments. This research paves the way for the engineering applications of acoustic micro-control, micro-nano fabrication, remote acoustic energy transmission manipulation, acoustic measurement, weak signal processing, acoustic flexible control and other micro-shape and multi-functional acoustic devices, and will bring more inspiration to other classical wave communication fields such as light wave, electromagnetic wave and so on.

The use of BRAF-inhibitors as monotherapy and in combination with cytosine arabinoside and 2-chloro-2’deoxyadenosine in pediatric patients with different forms of Langerhans cell histiocytosis

Background. Langerhans cell histiocytosis (LCH) is a rare disease that occurs due to abnormal proliferation and expansion of myeloid precursors. The occurrence of mutations in genes that encode key kinases of MAPK-signaling pathway leads to its pathological activation and has been shown the cause of disease. Mutations in BRAF and MAP2K1 genes are the most frequent among LCH patients. The effectiveness of BRAF-inhibitors in LCH patients has been shown in numerous studies.The purpose of the study – analyze the experience of BRAF-inhibitor vemurafenib administration as monotherapy and in combination with cytosine arabinoside (ARA-C) and 2-chloro-2'-deoxyadenosine (2-CdA) in pediatric patients with different forms of LCH.Materials and methods. Fifteen patients with various forms of LCH were enrolled in the study. BRAF mutations were detected in 14 patients, mutation in the MAP2K1 gene was detected in one case. Patients with “risk organ” (RO) involvement were included in the first group (n = 9). These patients received combined therapy with vemurafenib and ARA-C/2-CdA. Patients without RO involvement, included in group 2 (n = 6), received vemurafenib as monotherapy. The assessment of the response to the therapy in group 1 was carried out in accordance with the DAS scale, in group 2 in accordance with the RECIST v1.1. The toxicity assessment in both groups was carried out in accordance with the CTCAE v5.0.Results. All patients in group 1 achieved non-active disease status with a median of 35 (28–61) days. In group 2 partial response to vemurafenib was achieved in 5 cases. Relapse after targeted therapy termination was diagnosed in two patients. Photodermatitis was the most common side effect of targeted therapy.Conclusions. The use of vemurafenib was effective in both groups. There were no cases of grade III–IV toxicity according to CTCAE v5.0 associated with vemurafenib administration in this study. The combination of vemurafenib and ARA-C/2-CdA showed high efficacy and good tolerability in group 1. Two cases of disease relapse after targeted therapy cessation in group 2 show that the monotherapy approach does not always allow to achieve long-term remission in LCH patients.

Genome-scale metabolic network model and phenome of solvent-tolerant Pseudomonas putida S12

BackgroundPseudomonas putida S12 is a gram-negative bacterium renowned for its high tolerance to organic solvents and metabolic versatility, making it attractive for various applications, including bioremediation and the production of aromatic compounds, bioplastics, biofuels, and value-added compounds. However, a metabolic model of S12 has yet to be developed.ResultsIn this study, we present a comprehensive and highly curated genome-scale metabolic network model of S12 (iSH1474), containing 1,474 genes, 1,436 unique metabolites, and 2,938 metabolic reactions. The model was constructed by leveraging existing metabolic models and conducting comparative analyses of genomes and phenomes. Approximately 2,000 different phenotypes were measured for S12 and its closely related KT2440 strain under various nutritional and environmental conditions. These phenotypic data, combined with the reported experimental data, were used to refine and validate the reconstruction. Model predictions quantitatively agreed well with in vivo flux measurements and the batch cultivation of S12, which demonstrated that iSH1474 accurately represents the metabolic capabilities of S12. Furthermore, the model was simulated to investigate the maximum theoretical metabolic capacity of S12 growing on toxic organic solvents.ConclusionsiSH1474 represents a significant advancement in our understanding of the cellular metabolism of P. putida S12. The combined results of metabolic simulation and comparative genome and phenome analyses identified the genetic and metabolic determinants of the characteristic phenotypes of S12. This study could accelerate the development of this versatile organism as an efficient cell factory for various biotechnological applications.

Diversity of Epiphytic Subaerial Algal Communities in Bangkok, Thailand, and Their Potential Bioindicator with Air Pollution

Epiphytic subaerial algae represent an assemblage of micro-organisms widely distributed in terrestrial environments, including urban environments. Urban habitats present many challenges for the survival of photosynthetic micro-organisms, yet many species of subaerial microalgae have been reported from these environments, demonstrating a high tolerance to the harsh conditions of urban environments. In this study, the epiphytic subaerial communities of five parks in the urban area of Bangkok were studied using a metabarcoding approach (sequencing of the 23S rDNA marker), with the goal of unraveling their diversity and assessing potential bioindicators with levels of air pollution. Diversity indexes were determined for the algal taxa detected, which were separated into groups corresponding to different collection sites by cluster analysis. Relationships between taxa and air pollutants were analyzed by PCA and the Pearson correlation coefficient (r). The results showed a high diversity of epiphytic subaerial algae. We recorded 101 taxa belonging to the Cyanophyta (70 taxa), Chlorophyta (21 taxa), Charophyta (5 taxa), Bacillariophyta (3 taxa), and Eustigmatophyta (2 taxa). The most abundant taxon was Chroococcidiopsis sp. 1, for which up to 13,254 sequences/cm2 were recorded. The Shannon–Weaver index ranged between 1.37 and 2.51, the Margalef index between 3.84 and 4.75, and the Pielou index between 0.30 and 0.54. The similarity index was between 8.00% and 64.82%, according to the cluster analysis results for the three groups. The PCA indicated that all air pollutants affected the diversity and abundance of epiphytic subaerial algae. Cyanothece sp. 2 was negatively related to O3 and positively related to NO2 and CO and is suggested as a potential bioindicator of air pollution.

Facile colorimetric sensor using oxidase-like activity of octahedral Ag2O particles for highly selective detection of Pb(II) in water

Pb(II) is a prevalent heavy metal ion classified as a 2B carcinogen. Excessive intake of Pb(II) in the human body can damage the central nervous system, kidneys, liver, and immune system, leading to permanent brain damage, anemia, and cancer. Colorimetry can be applied to rapidly determine Pb(II) residues, but there are still many challenges in the accuracy and sensitivity of detection. Based on the inhibitory impact of Pb(II) on the oxidase-like activity of octahedral silver oxide (Ag2O), a colorimetric sensor with smartphone-assisted analysis for the Pb(II) detection was first developed. Herein, it has been found that Pb(II) can adsorb onto the surface of octahedral Ag2O, hindering the production of O2− in the reaction system. This ultimately results in the suppression of oxidase-like activity, leading to a lighter purple appearance of the colorimetric reaction solution. The sensor exhibits a high degree of sensitivity and a limit of detection (LOD) for Pb(II) was calculated as 2.2 μg L−1. Hence, the developed colorimetric sensor with high sensitivity, excellent specificity, and high tolerance to sodium ions is hopeful to have practical applications in Pb(II) detection in environmental water samples. Moreover, the sensor will provide a novel strategy for heavy metal ion detection and other substances.

Effectiveness of trichloroacetic acid versus electrocautery for the treatment of anal high-grade squamous intraepithelial lesions in persons with HIV

Purpose This study aimed to compare trichloroacetic acid (TCA) versus electrocautery (ECA) for the treatment of anal high-grade squamous intraepithelial lesions (HSIL). Methods This is an observational, single-center study. All subjects with HIV who had anal HSIL treated with TCA or ECA from 2010 to 2022 were included. Effectiveness was evaluated by on-treatment analysis, defining response as the resolution of HSIL and recurrence as a new diagnosis of HSILs during follow-up. A propensity score analysis was used to adjust for confounding factors. Results In total, 227 and 260 HSIL episodes were treated with ECA and TCA, respectively. Response was observed in 61.7% (95% CI: 55.3–68) of cases treated with ECA and in 73.1% (95% CI: 67.8–78.5) with TCA (p = .004). The effectiveness of TCA was higher in large and multifocal HSILs. Side effects were common with both treatments, but no serious events were described. Tolerability was good in 77.1% and 80.7% of patients treated with ECA and TCA, respectively. At 24 months, recurrent HSIL were observed in 36.3% (95% CI: 27.3–45) and 28% (95% CI: 20.2–35.8) in the ECA and TCA groups (p = .049). A nadir CD4 cell count ≤200 cells/µl was found to be a risk factor for recurrence (OR: 1.77; 95% CI: 1.12–2.78). Conclusions In this study, treatment with TCA showed high effectiveness, low recurrence and good tolerability. Considering the benefits of TCA, it could be considered one of the first-line treatments for anal HSIL.

Low-loss hollow-core fiber with stadium-shaped nested tubes for near-infrared communications

We propose a hollow-core fiber structure consisting of multilayer nested stadium-shaped tubes (HC-SSF), designed to reduce attenuation in the near-infrared bands for communications. The HC-SSF exhibits low loss characteristics, resulting in a four-order-of-magnitude attenuation reduction in confinement loss. The proposed HC-SSF achieves a confinement loss of 3.42×10−9 dB/m at 1.30 μm, while maintaining favorable single-mode characteristics and excellent bend resistance. At a bend radius of 8 cm, the HC-SSF demonstrates a bend-introduced loss of 1.72×10−7 dB/m at 1.30 μm. The total loss of HC-SSF remains below 0.1 dB/km within the 1.15 μm to 2.0 μm range. Due to its high fabrication tolerance and simple structure, the HC-SSF offers valuable reference for the extensive application of hollow-core fiber in the field of communication. It has a wide range of promising applications in gas and liquid sensing, and optical communications.

Long non-coding RNA LncCplx2 regulates glucose homeostasis and pancreatic β cell function

ObjectiveNumerous studies have highlighted the role of clock genes in diabetes disease and pancreatic β cell functions. However, whether rhythmic long non-coding RNAs involve in this process is unknown. MethodsRNA-seq and 3’ rapid amplification of cDNA ends (RACE)-PCR were used to identify the rat LncCplx2 in pancreatic β cells. The subcellular analysis with qRT-PCR and RNA-Scope were used to assess the localization of LncCplx2. The effects of LncCplx2 overexpression or knockout (KO) on the regulation of pancreatic β cell functions were assessed in vitro and in vivo. RNA-seq, immunoblotting (IB), Immunoprecipitation (IP), RNA pull-down, and chromatin immunoprecipitation (ChIP)-PCR assays were employed to explore the regulatory mechanisms through LncRNA-protein interaction. Metabolism cage was used to measure the circadian behaviors. ResultsWe first demonstrate that LncCplx2 is a conserved nuclear long non-coding RNA and enriched in pancreatic islets, which is driven by core clock transcription factor BMAL1. LncCplx2 is downregulated in the diabetic islets and repressed by high glucose, which regulates the insulin secretion in vitro and ex vivo. Furthermore, LncCplx2 KO mice exhibit diabetic phenotypes, such as high blood glucose and impaired glucose tolerance. Notably, LncCplx2 deficiency has significant effects on circadian behavior, including prolonged period duration, decreased locomotor activity, and reduced metabolic rates. Mechanistically, LncCplx2 recruits EZH2, a core subunit of polycomb repression complex 2 (PRC2), to the promoter of target genes, thereby silencing circadian gene expression, which leads to phase shifts and amplitude changes in insulin secretion and cell cycle genes. ConclusionsOur results propose LncCplx2 as an unanticipated transcriptional regulator in a circadian system and suggest a more integral mechanism for the coordination of circadian rhythms and glucose homeostasis.

Biogeography of Greater Antillean freshwater fishes, with a review of competing hypotheses.

In biogeography, vicariance and long-distance dispersal are often characterised as competing scenarios. However, they are related concepts, both relying on collective geological, ecological, and phylogenetic evidence. This is illustrated by freshwater fishes, which may immigrate to islands either when freshwater connections are temporarily present and later severed (vicariance), or by unusual means when ocean gaps are crossed (long-distance dispersal). Marine barriers have a strong filtering effect on freshwater fishes, limiting immigrants to those most capable of oceanic dispersal. The roles of vicariance and dispersal are debated for freshwater fishes of the Greater Antilles. We review three active hypotheses [Cretaceous vicariance, Greater Antilles-Aves Ridge (GAARlandia), long-distance dispersal] and propose long-distance dispersal to be an appropriate model due to limited support for freshwater fish use of landspans. Greater Antillean freshwater fishes have six potential source bioregions (defined from faunal similarity): Northern Gulf of México, Western Gulf of México, Maya Terrane, Chortís Block, Eastern Panamá, and Northern South America. Faunas of the Greater Antilles are composed of taxa immigrating from many of these bioregions, but there is strong compositional disharmony between island and mainland fish faunas (>90% of Antillean species are cyprinodontiforms, compared to <10% in Northern Gulf of México and Northern South America, and ≤50% elsewhere), consistent with a hypothesis of long-distance dispersal. Ancestral-area reconstruction analysis indicates there were 16 or 17 immigration events over the last 51 million years, 14 or 15 of these by cyprinodontiforms. Published divergence estimates and evidence available for each immigration event suggests they occurred at different times and by different pathways, possibly with rafts of vegetation discharged from rivers or washed to sea during storms. If so, ocean currents likely provide critical pathways for immigration when flowing from one landmass to another. On the other hand, currents create dispersal barriers when flowing perpendicularly between landmasses. In addition to high salinity tolerance, cyprinodontiforms collectively display a variety of adaptations that could enhance their ability to live with rafts (small body size, viviparity, low metabolism, amphibiousness, diapause, self-fertilisation). These adaptations likely also helped immigrants establish island populations after arrival and to persist long term thereafter. Cichlids may have used a pseudo bridge (Nicaragua Rise) to reach the Greater Antilles. Gars (Lepisosteidae) may have crossed the Straits of Florida to Cuba, a relatively short crossing that is not a barrier to gene flow for several cyprinodontiform immigrants. Indeed, widespread distributions of Quaternary migrants (Cyprinodon, Gambusia, Kryptolebias), within the Greater Antilles and among neighbouring bioregions, imply that long-distance dispersal is not necessarily inhibitory for well-adapted species, even though it appears to be virtually impossible for all other freshwater fishes.